1. Field of the Invention
The present invention relates to a method for increasing effectiveness of a chemotherapeutic or decreasing the resistance to a DNA damaging agent by inhibiting checkpoint kinase 1 on a specific dosing schedule.
2. Description of the State of Art
Checkpoint kinase 1 (“CHK1”) is a serine/threonine kinase. CHK1 regulates cell-cycle progression and is a main factor in DNA-damage response within a cell. CHK1 inhibitors have been shown to sensitize tumor cells to a variety of genotoxic agents, such as chemotherapy and radiation. (Tse, Archie N., et al., “Targeting Checkpoint Kinase 1 in Cancer Therapeutics.” Clin. Cancer Res. 13(7) (2007) 1955-1960). It has been observed that many tumors are deficient in the G1 DNA damage checkpoint pathway, resulting in the reliance on S and G2 checkpoints to repair DNA damage and survive. (Janetka, James W., et al., “Inhibitors of checkpoint kinases: From discovery to the clinic.” Drug Discovery & Development Vol. 10, No. 4 (2007) 473-486). The S and G2 checkpoints are regulated by CHK1. Inhibition of CHK1 has been shown to cancel the S and G2 checkpoints, thereby impairing DNA repair and resulting in increased tumor cell death. However, non-cancerous cells have a functioning G1 checkpoint, allowing for DNA repair and survival.
Checkpoint kinase 2 (“CHK2”) is also a serine/threonine kinase. CHK2's functions are central to the induction of cell cycle arrest and apoptosis by DNA damage. (Ahn, Jinwoo, et al., “The Chk2 protein kinase.” DNA Repair 3 (2004) 1039-1047). CHK2 is activated in response to genotoxic insults and propagates the checkpoint signal along several pathways, which eventually causes cell-cycle arrest in the G1, S and G2/M phases, activation of DNA repair, and apoptotic cell death. (Bartek, Jiri, et al., “CHK2 Kinase—A Busy Messenger.” Nature Reviews Molecular Cell Biology. Vol. 2(12) (2001) 877-886). Cancer cells often lack one or more genome-integrity checkpoints, so inhibition of CHK2 could make tumor cells selectively more sensitive to anti-cancer therapies, such as γ-radiation or DNA-damaging drugs. Normal cells would still activate other checkpoints and recover, while cancer cells deprived of checkpoints would be more likely to die. It has been demonstrated that a peptide-based inhibitor of CHK2 abrogated the G2 checkpoint and sensitized p53-defective cancer cells to DNA damaging agents. (Pommier, Yves, et al., “Targeting Chk2 Kinase: Molecular Interaction Maps and Therapeutic Rationale.” Current Pharmaceutical Design. Vol. 11, No. 22 (2005) 2855-2872).
CHK1 inhibitors are known, see for example, International Publication WO 2009/004329, International Publication WO 2008/012635, International Publication WO 2007/090493, International Publication WO 2007/090494, International Publication WO 2006/106326, International Publication WO 2006/120573, International Publication WO 2005/103036, International Publication WO 2005/066163 and International Publication WO 03/028724.
CHK1 inhibitors include SCH900776, PF-00477736, AZD7762, XL844 (see 2008 EORTC Poster #395 [http://www.exelixis.com/eortc/posters/EORTC08—395_XL844-002.pdf]), IC-83, and CHIR-124 (see Tse, Archie N., et al. “CHIR-124, a Novel Potent Inhibitor of Chk1, Potentiates the Cytotoxicity of Topoisomerase 1 Poisons In vitro and In vivo.” Clin. Cancer Res. 13(2) (2007) pp. 591-602).
U.S. Provisional Patent Application 61/052,926 describes compounds including (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (hereinafter “Compound 1”) and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (hereinafter “Compound 2”), (R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1′-1-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (hereinafter “Compound 3”), (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide (hereinafter “Compound 4”), (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (hereinafter “Compound 5”), (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide (hereinafter “Compound 6”), and (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (hereinafter “Compound 7”). Compounds 1, 2, 3, 4, 5, 6 and 7 (collectively the “926 CHK1 Inhibitors”) are CHK1 inhibitors.
CHK1 inhibitors have been tested as therapeutics for the treatment of diseases. Various dosing schedules have been used in these tests of inhibitors of mitosis. There remains a need for dosing regimens for CHK1 inhibitors that allows potent biological activity with manageable toxicity. There remains a particular need for dosing regimens for CHK1 inhibitors that allows for potentiation of DNA damaging agents dosed in the same regimen.